IRS1

Summary

IRS1 (insulin receptor substrate 1, HGNC:6125) is a protein-coding gene on chromosome 2q36.3, encoding Insulin receptor substrate 1 (P35568). Signaling adapter protein that participates in the signal transduction from two prominent receptor tyrosine kinases, insulin receptor/INSR and insulin-like growth factor I receptor/IGF1R.

This gene encodes a protein which is phosphorylated by insulin receptor tyrosine kinase. Mutations in this gene are associated with type II diabetes and susceptibility to insulin resistance.

Source: NCBI Gene 3667 — RefSeq curated summary.

At a glance

• GWAS associations: 72
• Clinical variants (ClinVar): 208 total — 2 pathogenic
• Phenotypes (HPO): 5
• Druggable target: yes
• MANE Select transcript: NM_005544

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6125
Approved symbol	IRS1
Name	insulin receptor substrate 1
Location	2q36.3
Locus type	gene with protein product
Status	Approved
Aliases	HIRS-1
Ensembl gene	ENSG00000169047
Ensembl biotype	protein_coding
OMIM	147545
Entrez	3667

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000305123, ENST00000498335, ENST00000918829

RefSeq mRNA: 1 — MANE Select: NM_005544 NM_005544

CCDS: CCDS2463

Canonical transcript exons

ENST00000305123 — 2 exons

Exon	Start	End
ENSE00001124681	226794989	226799820
ENSE00001136071	226731312	226736250

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 97.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.6771 / max 255.4446, expressed in 1429 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34327	6.1060	1232
34305	4.7513	620
34321	2.4300	560
34326	1.9286	1082
34325	1.0869	755
34309	0.7056	306
34324	0.7024	500
34328	0.5178	327
34323	0.3635	220
202592	0.3429	195

Top tissues by expression

297 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	97.04	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.04	gold quality
tibia	UBERON:0000979	94.95	gold quality
epithelium of mammary gland	UBERON:0003244	94.77	gold quality
mammary duct	UBERON:0001765	94.63	gold quality
cartilage tissue	UBERON:0002418	94.51	gold quality
vastus lateralis	UBERON:0001379	92.98	gold quality
decidua	UBERON:0002450	91.93	gold quality
biceps brachii	UBERON:0001507	91.85	gold quality
mammary gland	UBERON:0001911	91.83	gold quality
oviduct epithelium	UBERON:0004804	91.80	gold quality
thoracic mammary gland	UBERON:0005200	91.78	gold quality
stromal cell of endometrium	CL:0002255	91.62	gold quality
mucosa of urinary bladder	UBERON:0001259	91.18	gold quality
parietal pleura	UBERON:0002400	90.95	gold quality
quadriceps femoris	UBERON:0001377	90.68	gold quality
Brodmann (1909) area 23	UBERON:0013554	90.57	gold quality
germinal epithelium of ovary	UBERON:0001304	90.55	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	90.46	gold quality
cervix squamous epithelium	UBERON:0006922	90.35	gold quality
adrenal tissue	UBERON:0018303	90.24	gold quality
choroid plexus epithelium	UBERON:0003911	90.01	gold quality
periodontal ligament	UBERON:0008266	89.93	gold quality
fallopian tube	UBERON:0003889	89.75	gold quality
pleura	UBERON:0000977	89.69	gold quality
triceps brachii	UBERON:0001509	89.66	gold quality
mammalian vulva	UBERON:0000997	89.55	gold quality
visceral pleura	UBERON:0002401	89.32	gold quality
ovary	UBERON:0000992	89.11	gold quality
left ovary	UBERON:0002119	88.98	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.73

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ATF3, CEBPA, CTNNB1, EPAS1, ESR1, HBP1, MYOD1, NFKB2, PGR, PPARG, TFAP2A, TFAP2B

miRNA regulators (miRDB)

275 targeting IRS1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-656-3P	100.00	72.15	2788
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997

Literature-anchored findings (GeneRIF, showing 40)

• association between the Gly972Arg polymorphism in insulin receptor substrate-1 (IRS-1) and birth weight in a population-based sample of Brazilian newborns (PMID:11874945)
• Insulin receptor substrate 1 translocation to the nucleus by the human JC virus T-antigen (PMID:11877394)
• Nitric oxide regulates oestrogen-activated signalling pathways at multiple levels through cyclic GMP-dependent recruitment of insulin receptor substrate 1 in human breast cancer cells. (PMID:11978177)
• insulin sensitivity of glucose disposal and lipolysis: no influence of common genetic variants (PMID:12107745)
• Relationship of genotypes to phenotypic features of polycystic ovary syndrome (PMID:12213887)
• IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways (PMID:12351658)
• PTPL1/FAP-1 has a key role in the apoptotic process in human breast cancer cells independent of Fas but associated with an early inhibition of the insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway (PMID:12354757)
• genetic variants in the gene appear not to have a major role as modifier genes in familial combined hyperlipidemia (PMID:12370850)
• Data suggest that salicylic acid can reverse the inhibitory effects of TNFalpha on insulin signaling via insulin receptor substrate 1 (PMID:12409308)
• Constitutive IRS-1 activation is a common phenomenon in tumors. (PMID:12414625)
• In two cohorts ofobese Caucasian children, we measured insulin sensitivity and genotyped insulin receptor substrate IRS-1 and IRS-2 genes for the Arg972Gly and the Asp1057Gly variants, respectively. (PMID:12475767)
• Increased frequency of the G972R variant of the insulin receptor substrate-1 (irs-1) gene among girls with a history of precocious pubarche. Sex hormone-binding globulin concentrations were lower among girls heterozygous for G972R variant. (PMID:12477526)
• inhibition of insulin-stimulated insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase/Akt signaling pathway by Grb10 (PMID:12493740)
• role in modulating insulin-stimulated degradation by serine 312 phosphorylation (PMID:12510059)
• concluded that the IRS-1 protein is involved in the signalling pathway of the BCR-ABL tyrosine kinase (PMID:12560071)
• Data describe the expression of peroxisome proliferator-activated receptor gamma (PPAR gamma) co-activator 1, PPAR gamma, insulin receptor substrate-1, glucose transporter isoform-4, and mitochondrial uncoupling protein-1 in adipose tissue. (PMID:12565902)
• findings suggest a role for Arg(972) IRS-1 in conferring risk for the development of type 1 diabetes (PMID:12606535)
• Increased growth caused by IRS-1 over-expression is balanced by constitutive activation of pro-death mechanisms. (PMID:12763374)
• there is an increase of serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. (PMID:12765939)
• Carriers of the Gly972Arg variant of the IRS-1 gene are at a 25% increased risk of having Type 2 diabetes compared with non-carriers. (PMID:12819898)
• IRS-1 is stabilized in tumor cells, the IRS-1/Akt/GSK-3 pathway is upregulated, and improved cell survival is seen in the presence of IGF-I (PMID:12821935)
• the Arg(972) IRS-1 variant could contribute to the risk for atherosclerotic cardiovascular diseases associated with type 2 diabetes by producing a cluster of insulin resistance-related metabolic abnormalities. (PMID:12843189)
• Protein kinase C delta modulates the ability of the insulin receptor kinase to tyrosine-phosphorylate IRS-1. (PMID:14583092)
• IRS-1 has a role in insulin attenuation of platelet functions by interfering with cAMP suppression along with Gi (PMID:14602724)
• Both of the IRS proteins modulate VPF/VEGF expression in pancreatic cancer cells by different mechanistic pathways. (PMID:14604996)
• The association of variants in IRS1 with type 2 diabetes and type 2 diabetes-related phenotypes and the differential expression of IRS1 in adipocytes and skeletal muscle suggest a role of this gene in the pathogenesis of type 2 diabetes in Pima Indians. (PMID:14633864)
• The IRS-1 Gly972Arg polymorphism relates to higher fasting insulin levels and lower triglyceride levels. The impact of this genotype and its modification by overweight may be smaller than suggested previously. (PMID:14642408)
• ETV6-NTRK3.IRS-1 complex formation through the NTRK3 C terminus is essential for ETV6-NTRK3 transformation (PMID:14668342)
• None of the polymorphisms in INSR or IRS1 was associated with metabolic syndrome findings. (PMID:14693412)
• G972R IRS-1 polymorphism impairs insulin regulation of endothelial nitric oxide synthase in vascular endothelial cells. (PMID:14707024)
• These data indicate that both insulin receptor substrate (IRS)-1 and -3, but not IRS-2 or IRS-4, play key roles in the differentiation of brown adipocytes. (PMID:14966273)
• Association of this gene’s single nucleotide polymorphism with type 2 diabetes. (PMID:14988278)
• Activation of hexosamine pathway affects glucose-induced phosphorylation of IRS-1. Impairs coupling of IRS-1 and PI 3-kinase and activativates Akt/mammalian target of rapamycin/phosphorylated heat- and acid-stable protein-1/p70S6 kinase pathway. (PMID:15001544)
• AII, acting via the type 1 receptor, increases IRS-1 phosphorylation at Ser312 and Ser616 via JNK and ERK1/2, respectively, thus impairing the vasodilator effects of insulin mediated by the IRS-1/PI 3-kinase/Akt/eNOS pathway. (PMID:15044323)
• phosphorylation of Ser(318) by PKC-zeta might contribute to the inhibitory effect of prolonged hyperinsulinemia on IRS-1 function. (PMID:15069075)
• data demonstrate cell-specific alterations in IRS protein concentrations in theca cells from polycystic ovaries consistent with exaggerated amplification of the insulin signal & which may play a role in ovarian hyperandrogenism & thecal hyperplasia (PMID:15155816)
• Data show that in adipocytes the insulin receptor is localized to caveolae,and that part of insulin receptor substrate 1 (IRS1), the immediate downstream signal mediator, colocalizes with the insulin receptor in the plasma membrane and caveolae. (PMID:15182363)
• a lack of the Arg972 IRS1 polymorphism was found in the Parakana Indian population (PMID:15222685)
• By inducing endothelial dysfunction, the Arg(972) IRS-1 polymorphism may contribute to the genetic predisposition to develop cardiovascular disease. (PMID:15240653)
• Having at least one R allele (GR or RR) for IRS1 G972R was associated with an increased risk of colon cancer [odds ratio 1.4, 95% confidence interval (95% CI) 1.1-1.9] (PMID:15247132)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	irs1	ENSDARG00000054087
mus_musculus	Irs1	ENSMUSG00000055980
rattus_norvegicus	Irs1	ENSRNOG00000014597
drosophila_melanogaster	chico	FBGN0024248

Paralogs (2): IRS4 (ENSG00000133124), IRS2 (ENSG00000185950)

Protein

Protein identifiers

Insulin receptor substrate 1 — P35568 (reviewed: P35568)

All UniProt accessions (1): P35568

UniProt curated annotations — full annotation on UniProt →

Function. Signaling adapter protein that participates in the signal transduction from two prominent receptor tyrosine kinases, insulin receptor/INSR and insulin-like growth factor I receptor/IGF1R. Plays therefore an important role in development, growth, glucose homeostasis as well as lipid metabolism. Upon phosphorylation by the insulin receptor, functions as a signaling scaffold that propagates insulin action through binding to SH2 domain-containing proteins including the p85 regulatory subunit of PI3K, NCK1, NCK2, GRB2 or SHP2. Recruitment of GRB2 leads to the activation of the guanine nucleotide exchange factor SOS1 which in turn triggers the Ras/Raf/MEK/MAPK signaling cascade. Activation of the PI3K/AKT pathway is responsible for most of insulin metabolic effects in the cell, and the Ras/Raf/MEK/MAPK is involved in the regulation of gene expression and in cooperation with the PI3K pathway regulates cell growth and differentiation. Acts a positive regulator of the Wnt/beta-catenin signaling pathway through suppression of DVL2 autophagy-mediated degradation leading to cell proliferation.

Subunit / interactions. Interacts with UBTF and PIK3CA. Interacts (via phosphorylated YXXM motifs) with PIK3R1. Interacts with ROCK1 and FER. Interacts (via PH domain) with PHIP. Interacts with GRB2. Interacts with SOCS7. Interacts (via IRS-type PTB domain) with IGF1R and INSR (via the tyrosine-phosphorylated NPXY motif). Interacts with ALK. Interacts with EIF2AK2/PKR. Interacts with GKAP1. Interacts with DGKZ in the absence of insulin; insulin stimulation decreases this interaction. Found in a ternary complex with DGKZ and PIP5K1A in the absence of insulin stimulation. Interacts with SQSTM1; the interaction is disrupted by the presence of tensin TNS2. Interacts with NCK1 (via SH2 domain). Interacts with NCK2 (via SH3 domain). Interacts with SH2B1; this interaction enhances leptin-induced activation of the PI3-kinase pathway. Interacts with DVL2; this interaction promotes the Wnt/beta-catenin signaling pathway.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Serine phosphorylation of IRS1 is a mechanism for insulin resistance. Ser-307, Ser-312, Ser-315, and Ser-323 phosphorylations inhibit insulin action through disruption of IRS1 interaction with the insulin receptor INSR. Phosphorylation of Tyr-896 is required for GRB2-binding. Phosphorylated by ALK. Phosphorylated at Ser-270, Ser-307, Ser-636 and Ser-1101 by RPS6KB1; phosphorylation induces accelerated degradation of IRS1. Phosphorylated on tyrosine residues in response to insulin. In skeletal muscles, dephosphorylated on Tyr-612 by TNS2 under anabolic conditions; dephosphorylation results in the proteasomal degradation of IRS1. Ubiquitinated by the Cul7-RING(FBXW8) complex in a mTOR-dependent manner, leading to its degradation: the Cul7-RING(FBXW8) complex recognizes and binds IRS1 previously phosphorylated by S6 kinase (RPS6KB1 or RPS6KB2). Ubiquitinated by TRAF4 through ‘Lys-29’ linkage; this ubiquitination regulates the interaction of IRS1 with IGFR and IRS1 tyrosine phosphorylation upon IGF1 stimulation. S-nitrosylation at by BLVRB inhibits its activity.

Disease relevance. Type 2 diabetes mellitus (T2D) [MIM:125853] A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. The gene represented in this entry may be involved in disease pathogenesis.

Polymorphism. The Arg-971 polymorphism impairs the ability of insulin to stimulate glucose transport, glucose transporter translocation, and glycogen synthesis by affecting the PI3K/AKT1/GSK3 signaling pathway. The polymorphism at Arg-971 may contribute to the in vivo insulin resistance observed in carriers of this variant. Arg-971 could contribute to the risk for atherosclerotic cardiovascular diseases associated with non-insulin-dependent diabetes mellitus (NIDDM) by producing a cluster of insulin resistance-related metabolic abnormalities. In insulin-stimulated human endothelial cells from carriers of the Arg-971 polymorphism, genetic impairment of the IRS1/PI3K/PDPK1/AKT1 insulin signaling cascade results in impaired insulin-stimulated nitric oxide (NO) release and suggested that this may be a mechanism through which the Arg-971 polymorphism contributes to the genetic predisposition to develop endothelial dysfunction and cardiovascular disease. The Arg-971 polymorphism not only reduces phosphorylation of the substrate but allows IRS1 to act as an inhibitor of PI3K, producing global insulin resistance.

RefSeq proteins (1): NP_005535* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001849	PH_domain	Domain
IPR002404	IRS_PTB	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR039011	IRS	Family

Pfam: PF00169, PF02174

UniProt features (112 total): modified residue 30, strand 15, compositionally biased region 12, sequence variant 11, mutagenesis site 10, region of interest 9, short sequence motif 9, helix 6, sequence conflict 3, domain 2, cross-link 2, turn 2, chain 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
7PPM	X-RAY DIFFRACTION	1.48
7PPL	X-RAY DIFFRACTION	1.53
5U1M	X-RAY DIFFRACTION	1.8
1K3A	X-RAY DIFFRACTION	2.1
1QQG	X-RAY DIFFRACTION	2.3
6BNT	X-RAY DIFFRACTION	3.2
2Z8C	X-RAY DIFFRACTION	3.25
1IRS	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35568-F1	49.93	0.17

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (32): 3, 99, 270, 307, 312, 315, 323, 330, 345, 348, 419, 446, 453, 465, 527, 612, 616, 629, 632, 636 …

Mutagenesis-validated functional residues (10):

Position	Phenotype
307	impaired degradation by the cul7-ring(fbxw8) complex; when associated with a-312; a-527; a-636 and a-639.
312	impaired degradation by the cul7-ring(fbxw8) complex; when associated with a-307; a-527; a-636 and a-639.
527	impaired degradation by the cul7-ring(fbxw8) complex; when associated with a-307; a-312; a-636 and a-639.
612	induces irs1 degradation.
632	does not affect irs1 stability.
636	impaired degradation by the cul7-ring(fbxw8) complex; when associated with a-307; a-312; a-527 and a-639.
639	impaired degradation by the cul7-ring(fbxw8) complex; when associated with a-307; a-312; a-527 and a-636.
794	loss of phosphorylation by sik2.
1186	significantly reduced traf4-mediated ubiquitination; when associated with r-1189.
1189	significantly reduced traf4-mediated ubiquitination; when associated with r-1186.

Function

Pathways and Gene Ontology

Reactome pathways

38 pathways

ID	Pathway
R-HSA-109704	PI3K Cascade
R-HSA-112399	IRS-mediated signalling
R-HSA-112412	SOS-mediated signalling
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1266695	Interleukin-7 signaling
R-HSA-198203	PI3K/AKT activation
R-HSA-201556	Signaling by ALK
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-2428928	IRS-related events triggered by IGF1R
R-HSA-2586552	Signaling by Leptin
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-74713	IRS activation
R-HSA-74749	Signal attenuation
R-HSA-9603381	Activated NTRK3 signals through PI3K
R-HSA-9725370	Signaling by ALK fusions and activated point mutants
R-HSA-982772	Growth hormone receptor signaling
R-HSA-9842663	Signaling by LTK
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-166520	Signaling by NTRKs
R-HSA-168256	Immune System
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-199418	Negative regulation of the PI3K/AKT network
R-HSA-2219528	PI3K/AKT Signaling in Cancer
R-HSA-2404192	Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)
R-HSA-2428924	IGF1R signaling cascade
R-HSA-449147	Signaling by Interleukins
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers

MSigDB gene sets: 523 (showing top): PID_SHP2_PATHWAY, GOBP_LIPID_MODIFICATION, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_TRANSPORT, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_POLYSACCHARIDE_BIOSYNTHETIC_PROCESS, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, YAGI_AML_WITH_INV_16_TRANSLOCATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, SP3_Q3, GOBP_INSULIN_SECRETION

GO Biological Process (19): signal transduction (GO:0007165), positive regulation of cell population proliferation (GO:0008284), insulin receptor signaling pathway (GO:0008286), positive regulation of glucose metabolic process (GO:0010907), cytokine-mediated signaling pathway (GO:0019221), positive regulation of fatty acid beta-oxidation (GO:0032000), response to insulin (GO:0032868), cellular response to insulin stimulus (GO:0032869), glucose homeostasis (GO:0042593), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), positive regulation of glycogen biosynthetic process (GO:0045725), positive regulation of D-glucose import across plasma membrane (GO:0046326), negative regulation of insulin receptor signaling pathway (GO:0046627), positive regulation of insulin receptor signaling pathway (GO:0046628), negative regulation of insulin secretion (GO:0046676), insulin-like growth factor receptor signaling pathway (GO:0048009), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), cellular response to fatty acid (GO:0071398), positive regulation of signal transduction (GO:0009967)

GO Molecular Function (11): phosphotyrosine residue binding (GO:0001784), transmembrane receptor protein tyrosine kinase adaptor activity (GO:0005068), protein kinase C binding (GO:0005080), insulin receptor binding (GO:0005158), insulin-like growth factor receptor binding (GO:0005159), signaling receptor complex adaptor activity (GO:0030159), signaling adaptor activity (GO:0035591), SH2 domain binding (GO:0042169), phosphatidylinositol 3-kinase binding (GO:0043548), signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), insulin receptor complex (GO:0005899), caveola (GO:0005901), intracellular membrane-bounded organelle (GO:0043231)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Insulin receptor signalling cascade	3
IRS-mediated signalling	2
Signaling by Receptor Tyrosine Kinases	2
IRS-related events triggered by IGF1R	1
Intracellular signaling by second messengers	1
Signaling by Interleukins	1
Signaling by NTRK1 (TRKA)	1
PI3K/AKT Signaling in Cancer	1
IGF1R signaling cascade	1
Signal Transduction	1
MAPK1/MAPK3 signaling	1
Negative regulation of the PI3K/AKT network	1
Signaling by NTRK3 (TRKC)	1
Signaling by ALK in cancer	1
Cytokine Signaling in Immune system	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell surface receptor protein tyrosine kinase signaling pathway	3
signaling receptor binding	3
cellular anatomical structure	3
insulin receptor signaling pathway	2
regulation of insulin receptor signaling pathway	2
protein binding	2
intracellular anatomical structure	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cellular response to insulin stimulus	1
glucose metabolic process	1
regulation of glucose metabolic process	1
positive regulation of carbohydrate metabolic process	1
positive regulation of small molecule metabolic process	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
fatty acid beta-oxidation	1
regulation of fatty acid beta-oxidation	1
positive regulation of fatty acid oxidation	1
positive regulation of lipid catabolic process	1
response to peptide hormone	1
response to insulin	1
cellular response to peptide hormone stimulus	1
carbohydrate homeostasis	1
intracellular signaling cassette	1
glycogen biosynthetic process	1
regulation of glycogen biosynthetic process	1
positive regulation of macromolecule biosynthetic process	1
positive regulation of glycogen metabolic process	1
positive regulation of D-glucose transmembrane transport	1
regulation of D-glucose import across plasma membrane	1
D-glucose import across plasma membrane	1
negative regulation of signal transduction	1
negative regulation of cellular response to insulin stimulus	1

Protein interactions and networks

STRING

3932 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IRS1	INS	P01308	999
IRS1	IGF1	P01343	998
IRS1	IGF1R	P08069	998
IRS1	GRB2	P29354	997
IRS1	PIK3R1	P27986	995
IRS1	INSR	P06213	991
IRS1	SHC1	P29353	991
IRS1	PTPN11	Q06124	987
IRS1	IRS2	Q9Y4H2	970
IRS1	SRC	P12931	961
IRS1	PIK3CA	P42336	952
IRS1	AKT1	P31749	942
IRS1	SLC2A4	P14672	939
IRS1	LEP	P41159	928
IRS1	BECN1	Q14457	920

IntAct

140 interactions, top by confidence:

A	B	Type	Score
PIK3CA	PIK3R1	psi-mi:“MI:0914”(association)	0.960
IRS1	PIK3R1	psi-mi:“MI:0914”(association)	0.920
PIK3R1	IRS1	psi-mi:“MI:0915”(physical association)	0.920
IRS1	PIK3R1	psi-mi:“MI:0915”(physical association)	0.920
PIK3R1	IRS1	psi-mi:“MI:0914”(association)	0.920
PIK3CA	PIK3R2	psi-mi:“MI:0914”(association)	0.900

BioGRID (265): SIRT1 (Affinity Capture-Western), IRS1 (Reconstituted Complex), PIK3R1 (Far Western), IRS1 (Affinity Capture-Western), INSR (Reconstituted Complex), PIK3R3 (Two-hybrid), BCAR3 (Two-hybrid), NUMB (Two-hybrid), PIK3R1 (Two-hybrid), PELI1 (Two-hybrid), IRS1 (Affinity Capture-Luminescence), IRS1 (Affinity Capture-Luminescence), IRS1 (Affinity Capture-Luminescence), IRS1 (Affinity Capture-MS), IRS1 (Affinity Capture-Western)

ESM2 similar proteins: A5PMU4, A6QLU3, O89032, P35568, P35569, P35570, P81122, P84770, Q06649, Q13094, Q13191, Q13480, Q13625, Q1LY51, Q1LYG0, Q28224, Q3TTA7, Q4KM52, Q5NBX1, Q5RJW5, Q5TCZ1, Q60787, Q62415, Q6DFR2, Q6GQL0, Q6P4Y6, Q6ZNC4, Q80UZ0, Q8BM65, Q8BSM5, Q8C180, Q8CG79, Q8IVF5, Q8TEW8, Q8WU20, Q8WV28, Q8WWW8, Q91615, Q93073, Q96KQ4

Diamond homologs: B3MPN6, B3N946, B4HWI2, B4NZ70, O14654, P35568, P35569, P35570, P81122, P84770, Q28224, Q5RJW5, Q6P4Y6, Q91615, Q9DF49, Q9XTN2, Q9Y4H2, Q9Z0Y7

SIGNOR signaling

135 interactions.

A	Effect	B	Mechanism
IL4R	up-regulates	IRS1	phosphorylation
PIK3CA	“down-regulates activity”	IRS1
TNF	down-regulates	IRS1
MAPK8	down-regulates	IRS1	phosphorylation
MAPK9	down-regulates	IRS1	phosphorylation
MAPK1	“down-regulates activity”	IRS1	phosphorylation
MAPK3	“down-regulates activity”	IRS1	phosphorylation
PRKCD	down-regulates	IRS1	phosphorylation
PRKCZ	down-regulates	IRS1	phosphorylation
PRKCD	“down-regulates activity”	IRS1	phosphorylation
PLK1	“down-regulates activity”	IRS1	phosphorylation
sirolimus	up-regulates	IRS1
PRKCA	“down-regulates activity”	IRS1	phosphorylation
RPS6KB1	“down-regulates activity”	IRS1	phosphorylation
MAPK1	down-regulates	IRS1	phosphorylation
IGF1R	up-regulates	IRS1	phosphorylation
IRS1	“up-regulates activity”	PIK3CA	binding
RPS6KA1	“down-regulates quantity by destabilization”	IRS1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 59 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	8	119.4×	3e-13
Activation of BAD and translocation to mitochondria	6	101.5×	2e-09
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	89.6×	3e-09
PI3K events in ERBB2 signaling	5	74.6×	1e-07
Signaling by ERBB2 ECD mutants	5	74.6×	1e-07
GAB1 signalosome	5	70.5×	1e-07
Tie2 Signaling	5	66.8×	2e-07
Activation of BH3-only proteins	6	66.2×	1e-08

GO biological processes:

GO term	Partners	Fold	FDR
insulin receptor signaling pathway	9	39.1×	1e-09
phosphatidylinositol 3-kinase/protein kinase B signal transduction	8	33.0×	4e-08
epidermal growth factor receptor signaling pathway	6	29.2×	1e-05
cellular response to insulin stimulus	5	16.7×	1e-03
intracellular protein localization	7	14.4×	1e-04
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	7	10.8×	4e-04
positive regulation of MAPK cascade	6	9.5×	2e-03
positive regulation of cell migration	7	8.5×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

208 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	167
Likely benign	15
Benign	12

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
29760	NM_005544.3(IRS1):c.2164GGT[1] (p.Gly723del)	Pathogenic
29762	NM_005544.3(IRS1):c.1823C>G (p.Thr608Arg)	Pathogenic

SpliceAI

617 predictions. Top by Δscore:

Variant	Effect	Δscore
2:226736248:ATTCT:A	acceptor_loss	0.9700
2:226736250:TCT:T	acceptor_loss	0.9700
2:226736251:C:CC	acceptor_gain	0.9700
2:226736251:CTGAA:C	acceptor_loss	0.9700
2:226736252:T:A	acceptor_loss	0.9700
2:226736253:G:C	acceptor_loss	0.9600
2:226736249:TT:T	acceptor_gain	0.9500
2:226754419:C:CT	donor_gain	0.9400
2:226754420:T:TT	donor_gain	0.9400
2:226799676:T:TA	donor_gain	0.9400
2:226736199:TGGG:T	donor_gain	0.9200
2:226794970:TTGTC:T	donor_gain	0.9200
2:226799620:T:TA	donor_gain	0.9100
2:226736254:AAAA:A	acceptor_loss	0.9000
2:226799324:CCAG:C	donor_gain	0.8900
2:226736247:CATT:C	acceptor_gain	0.8700
2:226773803:G:A	donor_gain	0.8700
2:226791301:C:CA	donor_gain	0.8600
2:226771286:T:A	donor_gain	0.8400
2:226799673:T:TA	donor_gain	0.8400
2:226788643:CAAAG:C	acceptor_gain	0.8300
2:226793505:A:AC	acceptor_gain	0.8300
2:226737918:C:A	donor_gain	0.8000
2:226799670:T:TA	donor_gain	0.8000
2:226736568:A:C	donor_gain	0.7900
2:226794968:CTTTG:C	donor_gain	0.7900
2:226794969:TTTGT:T	donor_gain	0.7900
2:226736206:CCA:C	donor_gain	0.7800
2:226764398:G:C	donor_gain	0.7800
2:226766774:TAA:T	donor_gain	0.7800

AlphaMissense

8130 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:226797973:C:G	A256P	1.000
2:226797978:A:G	L254P	1.000
2:226797991:G:C	H250D	1.000
2:226798002:G:T	A246D	1.000
2:226798014:T:A	D242V	1.000
2:226798014:T:G	D242A	1.000
2:226798015:C:A	D242Y	1.000
2:226798015:C:G	D242H	1.000
2:226798026:A:C	M238R	1.000
2:226798026:A:T	M238K	1.000
2:226798028:C:A	W237C	1.000
2:226798028:C:G	W237C	1.000
2:226798030:A:G	W237R	1.000
2:226798030:A:T	W237R	1.000
2:226798032:A:G	F236S	1.000
2:226798038:C:A	G234V	1.000
2:226798038:C:T	G234E	1.000
2:226798039:C:A	G234W	1.000
2:226798039:C:G	G234R	1.000
2:226798039:C:T	G234R	1.000
2:226798044:C:T	G232E	1.000
2:226798045:C:A	G232W	1.000
2:226798045:C:G	G232R	1.000
2:226798045:C:T	G232R	1.000
2:226798060:G:T	R227S	1.000
2:226798062:C:A	G226V	1.000
2:226798062:C:T	G226D	1.000
2:226798063:C:A	G226C	1.000
2:226798063:C:G	G226R	1.000
2:226798073:G:C	F222L	1.000

dbSNP variants (sampled 300 via entrez): RS1000026810 (2:226736262 A>C), RS1000033144 (2:226785986 A>G), RS1000070469 (2:226781013 A>C), RS1000141989 (2:226782227 C>A), RS1000238787 (2:226732514 CTATA>C,CTA), RS1000318685 (2:226791657 G>A,C,T), RS1000348892 (2:226748450 A>C), RS1000381365 (2:226762593 A>T), RS1000411941 (2:226782908 G>C), RS1000412415 (2:226763063 C>G,T), RS1000426035 (2:226797434 G>A,C), RS1000488482 (2:226754866 A>G), RS1000557333 (2:226759712 T>C), RS1000603902 (2:226757765 A>T), RS1000605760 (2:226800040 C>A)

Disease associations

OMIM: gene MIM:147545 | disease phenotypes: MIM:125853, MIM:608097

GenCC curated gene-disease

Mondo (2): type 2 diabetes mellitus (MONDO:0005148), periventricular heterotopia with microcephaly, autosomal recessive (MONDO:0011966)

Orphanet (1): Nodular neuronal heterotopia (Orphanet:2149)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000855	Insulin resistance
HP:0003584	Late onset
HP:0005978	Type II diabetes mellitus
HP:0031819	Increased waist to hip ratio

GWAS associations

72 associations (top):

Study	Trait	p-value
GCST000478_1	Type 2 diabetes	9.000000e-12
GCST000712_8	Type 2 diabetes	5.000000e-20
GCST000755_22	HDL cholesterol	2.000000e-09
GCST000758_3	Triglycerides	2.000000e-08
GCST001128_1	Adiposity	4.000000e-11
GCST001463_8	Adiponectin levels	2.000000e-08
GCST001524_15	Visceral adipose tissue/subcutaneous adipose tissue ratio	4.000000e-06
GCST001526_7	Fasting blood insulin (BMI interaction)	2.000000e-14
GCST002063_1	Sexual dimorphism in anthropometric traits	2.000000e-07
GCST002216_14	Triglycerides	3.000000e-15
GCST002223_38	HDL cholesterol	2.000000e-17
GCST002352_57	Type 2 diabetes	7.000000e-09
GCST002726_10	Glucose homeostasis traits	7.000000e-07
GCST002897_29	Triglycerides	3.000000e-06
GCST002899_17	HDL cholesterol	3.000000e-10
GCST003435_11	Body fat percentage	1.000000e-12
GCST003435_21	Body fat percentage	1.000000e-09
GCST003435_26	Body fat percentage	2.000000e-12
GCST003435_32	Body fat percentage	2.000000e-10
GCST003658_4	Modified Stumvoll Insulin Sensitivity Index (model adjusted for BMI)	7.000000e-09
GCST004064_28	Waist-hip ratio	5.000000e-09
GCST004065_70	Waist circumference	1.000000e-12
GCST004210_2	Body fat percentage	3.000000e-08
GCST004232_22	HDL cholesterol levels	2.000000e-19
GCST004237_43	Triglyceride levels	2.000000e-14
GCST004495_115	BMI (adjusted for smoking behaviour)	2.000000e-07
GCST004497_112	Body mass index (joint analysis main effects and smoking interaction)	3.000000e-07
GCST004497_113	Body mass index (joint analysis main effects and smoking interaction)	2.000000e-06
GCST004499_45	BMI in non-smokers	5.000000e-07
GCST004499_46	BMI in non-smokers	4.000000e-07

EFO canonical traits (26, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0004502	adiponectin measurement
EFO:0004767	visceral:subcutaneous adipose tissue ratio
EFO:0004340	body mass index
EFO:0005951	sexual dimorphism
EFO:0004471	insulin sensitivity measurement
EFO:0007800	body fat percentage
EFO:0004343	waist-hip ratio
EFO:0004318	smoking behavior
EFO:0007789	BMI-adjusted waist circumference
EFO:0008002	physical activity measurement
EFO:0004995	lean body mass
EFO:0004980	appendicular lean mass
EFO:0004307	glucose tolerance test
EFO:0004467	insulin measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008343	sex interaction measurement
EFO:0009270	heel bone mineral density
EFO:0004344	birth weight
EFO:0009770	leucine measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0005000	leptin measurement
EFO:0009458	alcohol use disorder measurement
EFO:0007986	reticulocyte count
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
C564292	Heterotopia, Periventricular, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523219 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs115457081	Toxicity	3	cyclophosphamide;epirubicin;fluorouracil	Breast Neoplasms;Neutropenia
rs13431554	Efficacy	3	clopidogrel	Coronary Artery Disease;Diabetes Mellitus;Type 2
rs1801278	Efficacy	3	Drugs Used In Diabetes	Diabetes Mellitus;Type 2

PharmGKB variants

6 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1078533	IRS1		0.00	0
rs1801123	IRS1		0.00	0
rs1801278	IRS1	3	1.25	1	Drugs Used In Diabetes
rs2288586	IRS1		0.00	0
rs10205923	IRS1		0.00	0
rs13431554	IRS1	3	3.00	1	clopidogrel

Binding affinities (BindingDB)

6 measured of 6 human assays (6 total across all organisms); most potent 6 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-[(1-benzoyl-3-methyl-5-oxo-4H-pyrazol-4-yl)diazenyl]-N-pyrimidin-2-ylbenzenesulfonamide	KD	170 nM	US-9320734: Small molecule inhibitors of the pleckstrin homology domain and methods for using same
4-[[2-(4-chlorobenzoyl)-3-hydroxy-5-methyl-3,4-dihydropyrazol-4-yl]diazenyl]-N-pyrimidin-2-ylbenzenesulfonamide	KD	1450 nM	US-9320734: Small molecule inhibitors of the pleckstrin homology domain and methods for using same
4-[[1-(4-tert-butylbenzoyl)-3-methyl-5-oxo-4H-pyrazol-4-yl]diazenyl]-N-pyrimidin-2-ylbenzenesulfonamide	KD	1700 nM	US-9320734: Small molecule inhibitors of the pleckstrin homology domain and methods for using same
4-[[1-(4-chlorobenzoyl)-3-methyl-5-oxo-4H-pyrazol-4-yl]diazenyl]-N-pyrimidin-2-ylbenzenesulfonamide	KD	1740 nM	US-9320734: Small molecule inhibitors of the pleckstrin homology domain and methods for using same
4-[[1-(4-aminobenzoyl)-3-methyl-5-oxo-4H-pyrazol-4-yl]diazenyl]-N-pyrimidin-2-ylbenzenesulfonamide	KD	2200 nM	US-9320734: Small molecule inhibitors of the pleckstrin homology domain and methods for using same
4-[[1-(4-hydroxybenzoyl)-3-methyl-5-oxo-4H-pyrazol-4-yl]diazenyl]-N-pyrimidin-2-ylbenzenesulfonamide	KD	2400 nM	US-9320734: Small molecule inhibitors of the pleckstrin homology domain and methods for using same

ChEMBL bioactivities

6 potent at pChembl≥5 of 8 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.30	Kd	50	nM	CHEMBL1685056
7.30	Kd	50	nM	CHEMBL1681823
6.92	Kd	120	nM	CHEMBL4536878
6.82	Kd	150	nM	CHEMBL1685055
5.80	Kd	1600	nM	CHEMBL4530453
5.48	Kd	3300	nM	CHEMBL1572640

CTD chemical–gene interactions

141 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases phosphorylation, increases expression, decreases expression, affects binding, decreases phosphorylation (+4 more)	11
sodium arsenite	affects cotreatment, increases phosphorylation, affects binding, increases reaction, increases methylation (+5 more)	6
methylmercuric chloride	increases expression, affects cotreatment	4
bisphenol A	increases phosphorylation, decreases reaction, increases expression	4
Resveratrol	decreases reaction, increases expression, increases phosphorylation, affects binding, decreases activity (+1 more)	4
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases methylation, increases phosphorylation	4
Metformin	affects reaction, decreases expression, decreases reaction, decreases phosphorylation, increases expression	4
Quercetin	increases phosphorylation, decreases expression, affects cotreatment, affects phosphorylation, affects reaction (+1 more)	4
Cadmium Chloride	decreases expression, decreases reaction, increases abundance, increases phosphorylation, increases expression	4
Palmitic Acid	affects cotreatment, affects phosphorylation, decreases reaction, increases phosphorylation, increases abundance	4
Sirolimus	affects phosphorylation, increases reaction, affects binding, increases activity, decreases degradation (+5 more)	4
trichostatin A	affects cotreatment, increases expression	3
arsenite	increases expression, decreases reaction, decreases expression, decreases methylation	3
Arsenic Trioxide	decreases reaction, increases phosphorylation, decreases expression, affects response to substance	3
Fulvestrant	affects cotreatment, increases phosphorylation, decreases expression, decreases reaction, increases expression	3
Cisplatin	decreases expression, decreases response to substance	3
Doxorubicin	affects cotreatment, affects expression, decreases expression, increases expression	3
Glucose	increases reaction, increases phosphorylation, affects reaction, decreases phosphorylation, decreases expression (+3 more)	3
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, decreases reaction, increases expression, increases phosphorylation	3
Tobacco Smoke Pollution	decreases expression, increases expression	3
Valproic Acid	increases expression, affects cotreatment	3
Aflatoxin B1	decreases expression, decreases methylation	3
mercuric bromide	affects cotreatment, increases expression	2
(+)-JQ1 compound	decreases expression	2
Rosiglitazone	decreases reaction, increases phosphorylation, decreases phosphorylation	2
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Cadmium	decreases reaction, increases abundance, increases phosphorylation, increases expression	2
Calcitriol	increases expression	2
Dexamethasone	affects expression, decreases expression	2

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4482512	Binding	Binding affinity to recombinant human IRS1 PH domain expressed in Escherichia coli BL21 (DE3) by surface plasmon resonance assay	Inhibitors of grb2-associated binding protein 1 (gab1) and methods of treating cancer using the same

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2ZF	Abcam HEK293T IRS1 KO	Transformed cell line	Female
CVCL_D1WZ	Abcam A-549 IRS1 KO	Cancer cell line	Male
CVCL_D2BA	Abcam HCT 116 IRS1 KO	Cancer cell line	Male
CVCL_ST06	HAP1 IRS1 (-) 1	Cancer cell line	Male
CVCL_ST07	HAP1 IRS1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00006163	PHASE4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	PHASE4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	PHASE4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	PHASE4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	PHASE4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	PHASE4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	PHASE4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	PHASE4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	PHASE4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	PHASE4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	PHASE4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	PHASE4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	PHASE4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	PHASE4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	PHASE4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	PHASE4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	PHASE4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	PHASE4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	PHASE4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	PHASE4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	PHASE4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	PHASE4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	PHASE4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	PHASE4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	PHASE4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	PHASE4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	PHASE4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	PHASE4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	PHASE4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	PHASE4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	PHASE4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	PHASE4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes
NCT00241085	PHASE4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus